Keywords: Tuberculosis, Latency, DNA Repair, Microbiology, Biochemistry, Molecular Biology
Tuberculosis (TB) causes more deaths than almost any other infectious disease, with nearly 2 million deaths each year. It is estimated that one-third of the world's population is latently infected with the causative agent, Mycobacterium tuberculosis. The ability of M. tuberculosis to enter into a latent state is thought to be the reason for the prolonged period of treatment required to prevent relapse, since drugs currently available mainly target actively growing bacteria.
The vast pool of latently infected individuals is a constant source of disease and transmission, as factors weakening the immune response, such as HIV infection, lead to the emergence of active disease. There is evidence that M. tuberculosis is exposed to DNA-damaging conditions in the host during latent infection. It is hypothesized that M. tuberculosis possesses particularly efficient mechanisms of DNA repair, and that these systems are required for the longterm survival of M. tuberculosis within the host. This project aims to evaluate the importance of the mechanisms which maintain genome integrity for bacterial survival during persistence and to identify targets for future drug development.
The proposal integrates activities of internationally recognised groups in the field that have complementary expertise to facilitate the multidisciplinary approach required to optimally advance this programme of research. Identification of inhibitors of proteins required for persistence is likely to lead to the development of new drugs active against bacteria in the latent state. This would be of great value both to shorten the period required to cure the active disease and to treat latent infection in individuals at high risk of disease reactivation.
HIV/AIDS and tuberculosis are responsible for an unprecedented global health crisis, with devastating effects in developing countries. The increased susceptibility to TB caused by co-infection with HIV is fuelling the worldwide TB epidemic, and infection with TB is a significant cause of AIDS associated mortality in poor countries. The intimate association between these two major diseases represents a serious threat to the developing world. Effective treatment of active TB and any intervention aimed at reducing the reservoir of people latently infected with TB, will not only alleviate the burden of TB but will also improve quality of life in HIV infected individuals.
It is hypothesized that mycobacteria possess particularly efficient mechanisms of DNA repair to maintain genome integrity. This would allow them to survive hostile, DNA-damaging conditions, until reactivation growth. These systems presumably are of particular importance for the long-term survival of M. tuberculosis within the host. Identification of the mechanisms that govern chromatin stability in M. tuberculosis is a promising avenue for the development of new drugs active against bacteria in the latent state. These would be expected to be of general use both to shorten the time period required to treat active disease and to eradicate latent tuberculosis.
The results are expected to provide insight into the mechanisms governing latency and persistence, and to produce knowledge that bears the potential for new therapeutic and prophylactic interventions.
To establish a novel concept of therapeutic intervention, i.e. mechanisms of DNA-repair and genome integrity as a target for developing drugs for curing latent tuberculosis.
Erik C. Böttger / Burkhard Springer
Institut für Medizinische Mikrobiologie
University of Zurich, Gloriastrasse 30/32
Tel: +41 44 634 26 60 (direct) / +41 44 634 27 00 (main)
Fax: +41 44 634 49 06
|Official Address||Other Information|
|2||Menico Rizzi /
|Dipartimento di Scienze Chimiche,
Alimentari, Farmaceutiche e
University of Piemonte Orientale
Via Bovio 6
|Tel: +39 0321 375812 |
Fax: +39 0321 375821
E-mail: firstname.lastname@example.org / email@example.com
|3||Elaine Davis||MRC National Institute for Medical
The Ridgeway, Mill Hill
London, NW7 1AA
|Tel: +44 20 8816 2358
Fax: +44 20 8816 2564
|4||Kalappa Muniyappa||Department of Biochemistry
Indian Institute of Science
|Tel: +91 80 2360 0278 |
Fax: +91 80 2360 0814
|5||Andrea Degen Iseli /
|Tel: +41 44 271 3333
Fax: +41 44 271 3335
E-mail: firstname.lastname@example.org /